tbuckley/cabot-search huggingface dataset:
Correlation of tumor gene expression profile and gleason score (GS) in patients (pts) with metastatic prostate cancer.
Authors: Nicolas Sayegh, Nishita Tripathi, Beverly Chigarira, Yeonjung Jo, Vinay Mathew Thomas, Roberto Nussenzveig, Kamal Kant Kant Sahu, Haoran Li, Georges Gebrael, Clara Tandar, Divyam Goel, Nityam Rathi, Benjamin L. Maughan, Umang Swami, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2023)

235 Background: GS is the most powerful prognostic predictor in prostate adenocarcinoma. However, the underlying reasons of disease aggressiveness as a function of GS are currently unknown. Herein we sought to investigate the corresponding differences in gene expression profiles of pts with prostate adenocarcinoma with respect to GS. Methods: In this IRB approved retrospective study, eligibility criteria included histologically confirmed prostate adenocarcinoma and available RNA sequencing results from treatment naïve primary prostate tissue by a CLIA certified lab. Pts were categorized into two cohorts: low GS (GS &lt;8) and high GS (GS ≥ 8). The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) in order to identify pathways enriched in each cohort. All bioinformatic analyses were undertaken using R v4.2. Results: Fifty-seven pts were eligible, of which 13 had a GS &lt;8 and 44 had a GS ≥8. Tumor tissues with high GS had a significantly higher expression of genes involved in the immune pathways (e.g., inflammatory response, interferon-γ, allograft rejection, and interferon-α), epithelial-mesenchymal transition, KRAS signaling, E2F targets and G2M checkpoint (q for all &lt;0.01). The genes involved in the androgen response pathway were significantly more expressed in biopsies with a low GS (q&lt;0.01). Normalized enrichment scores are reported in the table. Differential individual gene expression profiles will be presented at the meeting. Conclusions: Pts with prostatic adenocarcinoma with a GS ≥8 demonstrated a different transcriptomic profile than those with a GS &lt;8. Higher GS tumor tissues had upregulated of inflammatory, proliferation, and KRAS signaling. Lower GS tumor tissues had upregulated androgen signaling pathway. These hypothesis-generating results upon external validation may provide the rationale for personalized therapy in men with prostatic cancer. [Table: see text]
Risk factors for treatment (tx) toxicity and discontinuation among patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) on androgen receptor targeted therapy (ART).
Authors: Zakaria Chakrani, George Slade Mellgard, Stephen Mccroskery, Nathaniel Saffran, Nicole Taylor, Bobby Chi-Hung Liaw, William K. Oh, Kai Tsao, Vaibhav G. Patel
Journal: Journal of Clinical Oncology (2023)

135 Background: mCRPC is associated with (a/w) increased mortality among prostate cancer pts and new and safe txs are needed. In recent clinical trials, ARTs improved survival outcomes within this population, however, a significant portion will go on to discontinue tx. We aim to describe reasons for ART tx discontinuation and to identify predictors a/w increased risk of tx discontinuation due to tx toxicity or death. Methods: We performed a single-institution retrospective review of mCRPC pts on ART between 2010 and 2021. We screened for demographics, medical history, ART course, and tx side-effects. Our primary aim was to identify risk factors for tx discontinuation due to toxicity or death. Our secondary aim was to describe ART discontinuation among mCRPC. Fisher’s Exact was used to identify significant predictors of tx discontinuation due to toxicity or death. Significant outcomes were included in a multivariate logistic regression to determine odds ratios. Results: 133 pts with mCRPC started and discontinued ARTs. Among this cohort, 27 pts (20.3%) discontinued tx due to death or toxicity. Reasons for tx discontinuation are described in the table below. Significant predictors of tx discontinuation due to toxicity or death on bivariate analysis included pt-reported sepsis, hypertension (htn), weakness, falls, ECOG ≥2, and hospitalization during tx. Adjusting for confounders, pt-reported falls (OR 2.35; [0.91-2.59]; p=0.009), htn (OR 2.06; [0.94-2.21]; p=0.027), and weakness (OR 1.63; [0.59-2.72]; p=0.007) were a/w an increased risk of pt tx discontinuation from toxicity or death. Conclusions: Our results illustrate that the majority of mCRPC pts discontinued tx due to progression of disease. The data also indicates that mCRPC pts reporting new onset htn, falls, or weakness were more likely to discontinue tx due to toxicity or death. Early monitoring of this population is warranted to prolong duration of tx and prevent unnecessary txs. [Table: see text]
Assessment of surgical complications in patients with metastatic clear cell renal cell carcinoma (mccRCC) receiving perioperative cabozantinib and nivolumab on Cyto-KIK clinical trial.
Authors: Karie Runcie, Moshe Chaim Ornstein, Biren Saraiya, Venkatesh Krishnamurthi, Byron H Lee, Christopher B. Anderson, Guarionex Joel DeCastro, James M. McKiernan, Matthew Dallos, Tina M. Mayer, Melanie Marron, Alexandria Kulik, Eric A. Singer, Mark N. Stein
Journal: Journal of Clinical Oncology (2023)

691 Background: The perioperative safety of cabozantinib and nivolumab in mccRCC, and the optimal timing to hold cabozantinib prior to surgery, are unknown. Methods: In this phase 2 trial, patients with mccRCC are given cabozantinib (40mg daily) and nivolumab (480mg q4 weeks) for 12 weeks prior to cytoreductive nephrectomy. Post-operatively, patients resume treatment with cabozantinib and nivolumab until disease progression. A 3+3 design was used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabozantinib and nephrectomy. Evaluable patients completed at least 10 of 14 cabozantinib doses prior to the pre-specified period of stopping pre-operative cabozantinib. Surgical complications assessed using the Clavien-Dindo classification system is a secondary endpoint of this study. Results: 16 patients have been enrolled and 14 completed nephrectomy to date. 12 (75%) of patients are male, 4 (25%) female, ages 44-77 years old with median age at diagnosis 58.5 years old. BMIs ranged from 17.8 kg/m2 to 39.3 kg/m2 with median BMI of 28.7kg/m2. 63% of patients were classified by IMDC as intermediate-risk and 37% as poor-risk disease. Dose reductions of cabozantinib occurred in 14% of patients who completed nephrectomy and cabozantinib held in 42% of nephrectomy patients during the course of treatment. Three evaluable patients completed nephrectomy within the 21-day interval and 5 within the 14-day interval after discontinuation of cabozantinib. There were no treatment-related surgical complications in patients who completed nephrectomy and there were no delays in resuming combination systemic therapy after surgery. Conclusions: Combination cabozantinib and nivolumab can be safely administered up to 14 days prior to cytoreductive nephrectomy. Clinical Trial Information: NCT04322955 Clinical trial information: NCT04322955 .
A prospective phase II trial of pembrolizumab plus lenvatinib in advanced adrenal cortical carcinoma after failure of platinum- and mitotane-based chemotherapy (ACCOMPLISH).
Authors: Inkeun Park, Minsuk Kwon, Kwonoh Park, Se Hoon Park, Joo-Hwan Park, Sang Joon Shin, Hyun-Jeong Shim, Tak Yun, Jae-Lyun Lee, Hyo Jin Lee, Wonyoung Choi
Journal: Journal of Clinical Oncology (2023)

TPS3 Background: Adrenal cortical carcinoma (ACC) is a very rare cancer with poor prognosis. For advanced ACC, systemic treatment options are limited. There has been only one randomized phase III clinical trial in which etoposide, doxorubicin, cisplatin, and mitotane (EDP-M) achieved statistically significant improvement in terms of objective response rate (ORR) and progression-free survival (PFS). However, after failure of EDP-M regimen, no universally accepted treatment option exists. In human ACC sample, vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) expression were higher than adrenal adenoma, and 10-20% of tumor cells and 70% of tumor infiltrating monocyte are PD-L1 positive. In retrospective review of cabozantinib in advanced ACC, cabozantinib demonstrated 19% of ORR and 16.2 weeks of median PFS. Also, in phase II clinical trial of pembrolizumab in advanced ACC, ORR of 14-23% were shown. Considering synergism of VEGFR tyrosine kinase inhibitors (TKIs) and immune check point inhibitors (ICIs) in other cancers, combination of VEGFR TKI and ICI is an attractive approach in advanced ACC. Methods: This is an open-label,single-arm,multi-center,investigator-initiated phase II trial of lenvatinib plus pembrolizumab in patients with advanced ACC who failed previous platinum and mitotane therapy (NCT 05036434). Using Simon’s optimal two-stage design, 10 patients will be enrolled initially in the first stage. If at least 2 or more patients achieve complete response or partial response, the trial will continue until enrollment of a total of 30 patients. Patients will receive 200 mg of pembrolizumab every 3 weeks intravenously and 20 mg of daily lenvatinib orally until disease progression, intolerable toxicity, or patients’ withdrawal of consent. Key eligibility criteria are age ≥ 19 years, ECOG PS 0-1, biopsy-proven ACC, disease progression despite cisplatin- and mitotane-based chemotherapy, measurable disease according to RECIST v1.1, no uncontrolled hypertension, adequate kidney, liver, and bone marrow function. Primary endpoint is ORR, and secondary endpoints include PFS, safety profile, overall survival, duration of response. Exploratory evaluation of tumor genomics and immune microenvironment by whole exome sequencing, single-cell RNA sequencing, and T cell receptor sequencing in correlation with response will be performed. Enrollment began in June 2022 and projected enrollment goal is 3 years. Clinical trial information: NCT05036434 .
Use of prostate cancer subtyping by gene expression to predict response to radiation and chemohormonal therapies.
Authors: Adam B Weiner, Yang Liu, Alexander K. Hakansson, Xin Zhao, James Alexander Proudfoot, JJ Haijing Zhang, R. Jeffrey Karnes, Robert Benjamin Den, Amar Upadhyaya Kishan, Robert Evan Reiter, Anis Hamid, Ashley Ross, Phuoc T. Tran, Melvin L.K. Lee Kiang Chua, Daniel Eidelberg Spratt, Gerhardt Attard, Tamara L. Lotan, Christopher J Sweeney, Elai Davicioni, Edward M. Schaeffer
Journal: Journal of Clinical Oncology (2023)

241 Background: We previously reported on the use of gene expression profiling to characterize four primary subtypes in an analysis of over 100,000 prostate cancer primary tumors. Here we examine these subtypes and response to radiation (RT) after prostatectomy or chemotherapy in addition to androgen deprivation therapy (ADT) in hormone-sensitive metastatic prostate cancer (mHSPC). Methods: We examined a 215-gene prostate subtyping classifier (PSC) which groups luminal and basal gene expression profiles into one of four subtypes; luminal differentiated (LD), luminal proliferating (LP), basal immune (BI) and basal neuroendocrine-like (BN). The log-rank method was used to compare (i) metastasis-free survival between patients who did and did not receive salvage RT in the META855 cohort of localized disease patients treated with radical prostatectomy (n=855) and the (ii) overall survival of patients on the Phase III mHSPC EA3805 CHAARTED trial of ADT or ADT + docetaxel chemotherapy (n=160). Results: After radical prostatectomy, patients with BI tumors derived benefit from RT in terms of metastasis-free survival ( P=9.23e-4) while those with other subtype tumors did not (Each Log-rank P≥0.5). Patients with metastatic disease and LP tumors derived benefit from docetaxel (Log-rank P=0.002) while those with other subtypes tumors did not (Log-rank P=0.2). Conclusions: Basal-luminal subtyping segments tumors by relevant biological processes with potential implications for identifying patients who benefit from salvage radiation post prostatectomy and addition of docetaxel to ADT in mHSPC.
Two-fraction stereotactic MRI-guided ablative radiotherapy with simultaneous boost to dominant intraprostatic lesion: Results from the 2SMART phase 2 trial.
Authors: Wee Loon Ong, Patrick Cheung, Hans T. Chung, William Chu, Jay Detsky, Stanley K. Liu, Gerard Morton, Ewa Szumacher, Chia-Lin Tseng, Danny Vesprini, Melanie Davidson, Ananth Ravi, Merrylee McGuffin, Liying Zhang, Alexandre Mamedov, Andrea Deabreu, Meghan Poon, Andrew Loblaw
Journal: Journal of Clinical Oncology (2023)

349 Background: Prostate stereotactic ablative radiotherapy (SABR) for localised prostate cancer is commonly delivered over 5 fractions. Focal boost to the dominant intraprostatic lesion (DIL) seen on multiparametric magnetic resonance imaging (mpMRI) is an approach for dose-escalation in prostate SABR. This is the first report of the outcomes of the 2SMART trial, a phase 2 single-arm study using 2-fraction prostate SABR with DIL boost. Methods: Men with low to intermediate risk prostate cancer were enrolled in the study. Three gold fiducial markers were inserted for image guidance. The clinical target volume (CTV) included the prostate gland, and the planning target volume (PTV) was a 2mm expansion antero-posterior and laterally, and 2.5mm supero-inferiorly. The DIL was contoured on fused mpMRI. The prescribed dose was 26Gy in 2 fractions (EQD2 110Gy, α/β of 1.4) to the CTV, and up to 32Gy in 2 fractions (EQD2 164Gy) to the DIL as long as the dose constraints for the organs at risks were not exceeded. Each fraction was delivered 1 week apart. Daily image guidance with cone-beam computed tomography was used pre- and post-treatment. The primary endpoint was acute (≤3 months) changes in quality of life (QOL), assessed using the EPIC questionnaire. Minimal clinically important change (MCIC) in QOL was defined as an EPIC score decrease of &gt;0.5 standard deviation of the baseline EPIC score for each domain. Secondary endpoints were acute and late toxicities (assessed using CTCAEv4), and biochemical failure (based on Phoenix criteria). Results: 30 men were enrolled in the study, of which 2 (7%) had low risk and 28 (93%) had intermediate risk prostate cancer. The median follow-up was 44 months (range: 39-49 months). The median PSA nadir was 0.2ng/mL, with median time to nadir of 37 months. One patient (3%) had biochemical failure at 44 months post-treatment. 1 (3%) and 17 (57%) had acute Grade 2 GU and GI toxicities, while 3 (10%) and 15 (50%) had late (&gt;6 months) Grade 2 GU and GI toxicities. No acute or late Grade ≥3 GU or GI was reported. 10 (33%), 6 (20%), and 3 (10%) men had acute MCIC in urinary, bowel and sexual domains respectively. 15 (50%), 9 (30%) and 13 (43%) had late MCIC in urinary, bowel and sexual domain respectively. Conclusions: Two-fraction prostate SABR with DIL boost is a safe approach for dose-escalation for localised prostate cancer, with minimal impact on acute QOL, and no grade 3-4 toxicities. Clinical trial information: NCT03588819 .
Impact of pre-existing anemia and/or packed red blood cell transfusion prior to Radium-223 administration on oncologic outcomes.
Authors: Michael Pierro, Ariel Ann Nelson, John Xie, Albert Jang, Kathryn A. Bylow, Pedro C. Barata, Colleen Anne Lawton, Deepak Kilari
Journal: Journal of Clinical Oncology (2023)

67 Background: Radium-223 (Ra-223), a targeted alpha-emitting radiopharmaceutical approved for the treatment of metastatic prostate cancer (mPC), can cause myelosuppression. In the ALSYMPCA trial 30% of patients developed cytopenias, including 13% with grade 3/4 anemia. Therefore, it is recommended that only men with a hemoglobin ≥10 g/dL, platelet count ≥100,000/mm3, and ANC ≥1,500/mm3 be considered for Ra-223. Since the FDA approval of Ra-223 in 2013, several new treatments have been approved for men with mPC. With the changing therapeutic landscape, we anticipate more patients (pts) will have preexisting cytopenia prior to Ra-223 consideration. Hence, clinicians are increasingly likely to face the dilemma of whether it is safe and efficacious to administer Ra-223 in the setting of Hgb ≤10 with/without RBC transfusion support. Methods: We retrospectively identified pts with mPC treated with Ra-223, including a subset of men with Hgb &lt;10g/dl at the Medical College of Wisconsin and Tulane Cancer Center from 2014 – 2019. Clinical data including demographics, prior cancer treatments, laboratory data, blood product transfusion data, and oncologic outcomes were collected. Survival was estimated using Kaplan-Meier method and statistical analysis was conducted using student’s t-test. Results: Sixty-two pts were identified. Median age at the time of Ra-223 was 75.3 years. Of these, nearly 20% (n=12) had a Hgb &lt;10 g/dL and/or received RBC transfusions to meet “eligibility criteria” prior to beginning Ra-223 treatments. Compared to men who had Hgb &gt;10g/dL, men with Hgb &lt;10g/dL required more RBC transfusions both during and after Ra-223 treatment and had significantly worse oncologic outcomes. No patients experienced treatment delays of more than 1 week. There were no significant differences in the median number of treatments prior to Ra-223, median number of Ra-223 treatments received, platelet count nadir, or ANC nadir. Conclusions: Pre-existing Hgb &lt; 10 g/dl and/or RBC transfusions prior to Ra-223 therapy is associated with worse oncologic outcomes in mPC, suggesting that the benefit of Ra-223 is limited in this subset. A larger sample size is needed to further validate our findings. Multivariable analysis is planned. [Table: see text]
Implementing <sup>18</sup>F-DCFPyL PET in clinical practice: Prescribing patterns and utilization at a large academic center.
Authors: Miles Hsu, Xinhe Shan, Samuel U Takvorian, Austin Pantel, Vivek Narayan, Jeffrey Shevach, Neha Vapiwala, David J. Vaughn, Naomi B. Haas
Journal: Journal of Clinical Oncology (2023)

42 Background: 18 F-DCFPyL imaging was recently approved for initial staging in patients (pts) with prostate cancer and suspected metastasis and for those with biochemical recurrence (BCR). 18 F-DCFPyL recently became available at our NCI-Designated Comprehensive Cancer Center comprising 6 teaching hospitals and 2 outpatient facilities. As real-world data on 18 F-DCFPyL usage in the US are lacking, our objective was to describe prescription patterns and utilization for 18 F-DCFPyL. Methods: We identified 18 F-DCFPyL scans performed at our center from 1/1/2022-5/10/2022 and abstracted corresponding clinical data through electronic medical record (EMR) review. Demographic, laboratory, pathological and clinical data and provider-level usage were characterized by review of the EMR and, if necessary and feasible, provider interview. Results: There were 164 18 F-DCFPyL scans performed across the study period for 164 unique pts (median age 70 years, 73.8% White, 20.1% Black). Ordering providers belonged to Medical Oncology (54.3%), Radiation Oncology (42.7%), Urology (2.4%), and Nuclear Medicine (1%). The majority of scans were ordered for isolated PSA rise (n=93, 56.7%) and initial staging (n=26, 15.9%), in concordance with FDA-approved indications. Nevertheless, many scans were ordered for alternate indications. Restaging of pts with known refractory or metastatic disease (11.0%), PSA persistence after definitive therapy (8.5%), and PSA rises below the threshold of BCR (4.9%) were common alternate rationales for imaging. A minority of scans had a secondary indication such as RT field planning, distinguishing between two primary cancers, PSA persistence in high-risk disease, possible radioisotope therapy, and, most frequently, clarification of lesions seen on conventional imaging (n = 7). 22 pts were on androgen-deprivation (ADT, n=17) or anti-androgens (AR, n=11) when receiving PSMA imaging, with 5 pts on both; the median testosterone at time of imaging was &lt;20 ng/dL. Indeterminate lesions, defined as tracer avid with uncertain malignant status, were most often found in lymph nodes (n = 22) and focal rib lesions (n = 17), of which 12 were solitary, 3 were multifocal and 2 were superimposed on fractures. Conclusions: Shortly after adoption at a large cancer center, 18 F-DCFPyL has been prescribed in various clinical settings outside of FDA approvals. Around 1/8 were performed with pts on ADT/AR, with testosterone at castrate levels. Findings of uncertain malignant etiology included solitary (7%) and multifocal (2%) rib lesions. These data reveal substantial variability in usage and areas of uncertainty in the interpretation of 18 F-DCFPyL imaging in real-world clinical settings, underlining the need for further studies on its potential usefulness in expanded indications.
Effects of docetaxel on circulating immune cell subsets and association with outcomes in metastatic castration-sensitive prostate cancer.
Authors: Elias Chandran, Meghali Goswami, Renee Nicole Donahue, Mohammad O. Atiq, Fatima Karzai, Marijo Bilusic, Jennifer L. Marte, Philip M. Arlen, Lisa M. Cordes, Helen Owens, Megan Hausler, Amy Hankin, Monique Williams, William L. Dahut, William Douglas Figg, Jeffrey Schlom, James L. Gulley, Ravi Amrit Madan
Journal: Journal of Clinical Oncology (2023)

207 Background: Docetaxel with androgen deprivation therapy (ADT) has been shown to improve survival in metastatic castration-sensitive prostate cancer (mCSPC). There is limited data on the immunologic effects of docetaxel in mCSPC. Greater knowledge of the immune impact of docetaxel could inform future trials in prostate cancer. Methods: A clinical trial in mCSPC evaluated sequencing docetaxel and ADT with Prostvac, a poxviral vaccine targeting prostate-specific antigen (PSA). Eligibility criteria included mCSPC within 4 months of ADT and ECOG performance status 0-2. Patients given 6 cycles of docetaxel 75mg/m 2 with ADT alone for mCSPC were included in this analysis. Peripheral blood mononuclear cells (PBMCs) were sampled at baseline and at 3 weeks after commencing docetaxel. Immune cell subsets analyzed included CD4+ and CD8+ T-cells, T regulatory cells (Tregs), natural killer (NK) cells, dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs). Analyses were performed to determine if the baseline immune status or immune changes induced by therapy associate with PSA at 2 years. Results: Fifteen patients were evaluated for peripheral immune responses in this study. Median age was 63 years (range 50-73). Fourteen were white and 1 was black. ECOG performance status was 0 in 11 patients, 1 in 4 patients. Disease volume was high in 7 and low in 8 patients. Among 158 immune cell subsets assessed, only changes in Tregs and activated NK cells with a lytic and cytokine producing phenotype (CD16+ CD56br) were noted after initiation of docetaxel in addition to ADT. Patients with PSA ≤0.2 at 2 years had higher baseline frequencies of total CD4+ T cells, several activated CD4+ T-cell subsets, plasmacytoid DCs, and CD49d- Tregs. They also had lower baseline frequencies of total CD8+ T cells, naïve CD8+ T cells, and CD73+CD8+ T-cells. Patients with PSA ≤0.2 at 2 years also had greater percent increases in CD8+ effector memory (EM) PD-1+ T-cells after treatment. Conclusions: This is the first study to demonstrate increases in activated NK cells with lytic and cytokine producing potential after treatment with docetaxel. Given that NK cells are associated with clinical outcomes in prostate cancer (Zhao SG, JNCI, 2019) and that increased NK cells were seen after treatment with enzalutamide as well (Madan, JITC, 2021), developing immunotherapy combinations to capitalize on NK cell activity may be a path forward for developing immunotherapy in prostate cancer. Clinical trial information: NCT02649855 . [Table: see text]